Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids

Conventional nonsteroidal anti-inflammatory drugs inhibit both cyclooxygena se (Cox) isoforms (Cox-1 and Cox-2) and may be associated with nephrotoxici ty. The present study was undertaken to assess the renal effects of the spe cific Cox-2 inhibitor, MK-966. Healthy older adults (n = 36) were admitted to a clinical research unit, placed on a fixed sodium intake, and randomize d under double-blind conditions to receive the specific Cox-2 inhibitor, MK -966 (50 mg every day), a nonspecific Cox-1/Cox-2 inhibitor, indomethacin ( 50 mg t.i.d.), or placebo for 2 weeks. All treatments were well tolerated. Both active regimens were associated with a transient but significant decli ne in urinary sodium excretion during the first 72 h of treatment. Blood pr essure and body weight did not change significantly in any group. The glome rular filtration rate (GFR) was decreased by indomethacin but was not chang ed significantly by MK-966 treatment. Thromboxane biosynthesis by platelets was inhibited by indomethacin only. The urinary excretion of the prostacyc lin metabolite 2,3-dinor-6-keto prostaglandin F-1 alpha was decreased by bo th MK-966 and indomethacin and was unchanged by placebo. Cox-2 may play a r ole in the systemic biosynthesis of prostacyclin in healthy humans. Selecti ve inhibition of Cox-2 by MK-966 caused a clinically insignificant and tran sient retention of sodium, but no depression of GFR. Inhibition of both Cox isoforms by indomethacin caused transient sodium retention and a decline i n GFR. Our data suggest that acute sodium retention by nonsteroidal anti-in flammatory drugs in healthy elderly subjects is mediated by the inhibition of Cox-2, whereas depression of GFR is due to inhibition of Cox-1.